CN1964701A - 可直接压制的磷酸三钙 - Google Patents
可直接压制的磷酸三钙 Download PDFInfo
- Publication number
- CN1964701A CN1964701A CNA2005800144628A CN200580014462A CN1964701A CN 1964701 A CN1964701 A CN 1964701A CN A2005800144628 A CNA2005800144628 A CN A2005800144628A CN 200580014462 A CN200580014462 A CN 200580014462A CN 1964701 A CN1964701 A CN 1964701A
- Authority
- CN
- China
- Prior art keywords
- tricalcium phosphate
- aggregate
- pbw
- granule
- binding agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 235000019731 tricalcium phosphate Nutrition 0.000 title claims abstract description 49
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 48
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 47
- 229910000391 tricalcium phosphate Inorganic materials 0.000 title claims abstract description 47
- 229940078499 tricalcium phosphate Drugs 0.000 title claims abstract description 46
- 229920002907 Guar gum Polymers 0.000 claims abstract description 32
- 239000000665 guar gum Substances 0.000 claims abstract description 32
- 235000010417 guar gum Nutrition 0.000 claims abstract description 32
- 229960002154 guar gum Drugs 0.000 claims abstract description 32
- 239000011230 binding agent Substances 0.000 claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims description 78
- 239000008187 granular material Substances 0.000 claims description 28
- 238000009472 formulation Methods 0.000 claims description 24
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 19
- 239000011575 calcium Substances 0.000 claims description 18
- 229910052791 calcium Inorganic materials 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 235000015872 dietary supplement Nutrition 0.000 claims description 15
- 239000000314 lubricant Substances 0.000 claims description 12
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- 238000009826 distribution Methods 0.000 claims description 6
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- 238000010998 test method Methods 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
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- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 102100037179 Ubiquitin carboxyl-terminal hydrolase 25 Human genes 0.000 description 2
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- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
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- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
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- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
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- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
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- 241000416162 Astragalus gummifer Species 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
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- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102100037180 Ubiquitin carboxyl-terminal hydrolase 26 Human genes 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- GZCGUPFRVQAUEE-UHFFFAOYSA-N alpha-D-galactose Natural products OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
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- 229920001222 biopolymer Polymers 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
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- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
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- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
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- 235000013681 dietary sucrose Nutrition 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 239000011574 phosphorus Substances 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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Abstract
本发明的可压制的磷酸三钙团聚体含有磷酸三钙颗粒和粘结剂,每一个所述磷酸三钙颗粒都具有外表面,而所述的粘结剂包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶,并且该粘结剂承载在至少一部分所述磷酸三钙颗粒的至少一部分所述外表面上。
Description
技术领域
本发明涉及用于直接压制型片剂的磷酸三钙。
背景技术
磷酸三钙在药物应用中广泛地用作赋形剂。
确立了同时提供钙和磷的矿物质类膳食补充剂的价值的近期研究使人们对生产诸如片剂或囊片之类的口服制剂(包括咀嚼型口服制剂(诸如咀嚼片))给予了关注,其中磷酸三钙是这些制剂中的主要成分。
然而,使用磷酸三钙作为口服制剂主要成分的尝试导致形成的片剂表现出不合乎要求的低硬度。此外,用磷酸三钙制成的咀嚼片表现出令人不快的口感,这种感觉可描述为“砂砾感”或“粉质感(chalky)”。
人们需要的是制造含有较高含量的磷酸三钙并具有良好性质(包括可接受的硬度)的口服制剂的方法。此外,如果这种片剂被设计成咀嚼片,则需要其具有可接受的感觉品质,包括好的口感,而没有砂砾感和粉质感。
发明概述
在第一个方面中,本发明涉及可压制的磷酸三钙团聚体,该团聚体包含:
磷酸三钙颗粒,每一个所述颗粒都具有外表面;以及
粘结剂,该粘结剂包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶,并且该粘结剂承载在至少一部分所述磷酸三钙颗粒的至少一部分所述外表面上。
在第二个方面中,本发明涉及制造可压制的磷酸三钙团聚体的方法,该方法包括:对磷酸三钙和粘结剂(包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶)的水溶液进行喷雾干燥。
在第三个方面中,本发明涉及可直接压制的钙类膳食补充剂组合物,每100重量份(“pbw”)的所述组合物含有:
约20pbw到约80pbw的团聚体,该团聚体包含磷酸三钙颗粒(每一个颗粒都具有外表面)和粘结剂(包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶),所述粘结剂承载在至少一部分所述磷酸三钙颗粒的至少一部分所述外表面上;
约79pbw到约10pbw的除所述团聚体以外的含钙物质的颗粒;
约0.5pbw到约8pbw的崩解剂;以及
约0.5pbw到约2pbw的润滑剂。
在第四个方面中,本发明涉及制造钙类膳食补充剂组合物的口服制剂的方法,该方法包括对上述可直接压制的钙类膳食补充剂组合物进行压制。
在第五个方面中,本发明涉及一种钙类膳食补充剂组合物的口服制剂,该口服制剂是通过对上述可直接压制的钙类膳食补充剂组合物进行压制而制成的。
发明详述和优选实施方案
任何满足《美国药典》(第26卷)(“USP/NF 26”)或《食品化学法典》(第5版)(由位于美国哥伦比亚特区华盛顿市的美国国家科学院出版)(“FCC(第5版)”)规定的磷酸三钙都适于用作本发明团聚体的成分。在一个实施方案中,磷酸三钙表现出这样的粒度分布:其中少于或等于2重量%(“wt%”)、更通常为少于或等于0.6wt%的颗粒,具有大于140目(约100μm)的粒径,并且少于或等于5wt%、更通常为少于或等于2wt%的颗粒,具有小于325目(约50μm)的粒径。
本文中所使用的术语“粘结剂”是指能够将本发明组合物中的酸性成分和碱性成分的混合物紧密地结合成结实的粘结块的物质。合适的粘结剂化合物包括(例如)聚乙烯吡咯烷酮、瓜尔豆胶、阿拉伯胶、黄芪胶、明胶、多糖(例如葡萄糖和蔗糖)、淀粉、预糊化淀粉、鹿角菜胶和纤维素类物质、以及上述任何物质的混合物,所述纤维素类物质包括甲基纤维素和羧甲基纤维素、以及羟基烷基纤维素化合物(例如羟丙基甲基纤维素、羟丙基纤维素和羟乙基纤维素)。
在一个实施方案中,使用聚乙烯吡咯烷酮作为粘结剂。合适的聚乙烯吡咯烷酮是平均分子量大于或等于约30,000的那些聚乙烯吡咯烷酮。在一个实施方案中,聚乙烯吡咯烷酮粘结剂的平均分子量(Mw)约大于60,000或等于约60,000,更通常大于或等于约80,000。
在另一个实施方案中,使用瓜尔豆胶、改性的瓜尔豆胶或它们的混合物作为粘结剂。瓜尔豆胶是指豆科植物瓜尔豆的研磨胚乳的水溶性部分。该瓜尔豆胶由(1,4)-β-D-吡喃甘露糖基单元与α-D-吡喃半乳糖基单元通过(1,6)键连接而形成的直链构成,并且D-半乳糖与D-甘露糖的比例为约1∶2。瓜尔豆胶可以形成为可分散于热水或冷水中的白色粉末形式。改性的瓜尔豆胶包括(例如)羧甲基瓜胶、羧甲基羟丙基瓜胶、阳离子型羟丙基瓜胶、羟基烷基瓜胶(包括羟乙基瓜胶、羟丙基瓜胶、羟丁基瓜胶以及烷基碳原子数更高的羟基烷基瓜胶)和羧基烷基瓜胶(包括羧甲基瓜胶、羧丙基瓜胶、羧丁基瓜胶以及烷基碳原子数更高的羧基烷基瓜胶)。合适的瓜尔豆胶是下述这样的瓜尔豆胶和改性的瓜尔豆胶:其满足FCC(第5版)的规定并形成粘度足够低的溶液,从而使其能够用于喷雾干燥的方法中。在一个实施方案中,瓜尔豆胶的平均分子量小于或等于约2,000,000道尔顿,更通常的是其平均分子量为约200,000道尔顿到约2,000道尔顿。
在一个实施方案中,每100pbw的本发明的团聚体含有:
约90pbw到约99pbw、更通常为约93pbw到约98pbw、甚至更通常为约95pbw到约97pbw的磷酸三钙;以及
约10pbw到约1pbw、更通常为约7pbw到约2pbw、甚至更通常为约5pbw到3pbw的粘结剂。
磷酸三钙和粘结剂的团聚体可通过任何合适的团聚技术来制备,该团聚技术包括搅拌团聚技术(例如流化床干燥和高剪切混合)、加压团聚技术(例如压制)或喷雾团聚技术(例如喷雾干燥)。
在一个实施方案中,磷酸三钙和粘结剂的团聚体是通过对磷酸三钙和粘结剂的水溶液进行喷雾干燥而制成的。
在一个实施方案中,团聚体颗粒表现出这样的粒度分布:其中少于或等于65重量%(“wt%”)、更通常为90wt%的颗粒具有大于325目(约50μm)的粒径,并且少于或等于10wt%、更通常为2wt%的颗粒具有小于60目(约200μm)的粒径。
磷酸三钙和粘结剂的团聚体可以与其它成分(例如含钙物质的颗粒、润滑剂、崩解剂和助流剂)混合,从而形成合适的混合物,以便提供本发明的可直接压制的磷酸三钙组合物。
在一个实施方案中,本发明的可直接压制的钙类膳食补充剂组合物还包含一种或多种除本发明的团聚体以外的含钙物质的颗粒。合适的含钙物质包括钙鳌合物(例如蛋白钙)和钙盐(例如碳酸钙、葡萄糖酸钙、柠檬酸钙、磷酸三钙或二水磷酸二钙或无水磷酸二钙、以及柠檬酸苹果酸钙)。
在一个实施方案中,所述组合物所包含的磷酸三钙颗粒表现出这样的粒度分布:其中少于或等于15wt%、更通常为2.6wt%的颗粒具有大于40目(约300μm)的粒径,并且少于或等于5wt%、更通常为0.9wt%的颗粒具有小于325目(约50μm)的粒径。
在一个实施方案中,本发明的可直接压制的钙类膳食补充剂组合物还包含润滑剂。本文中所使用的术语“润滑剂”是指能够减少本发明的组合物与装置表面之间的摩擦的物质,所述装置用于将组合物紧密地压成压制品。合适的润滑剂包括(例如)脂肪酸(诸如软脂酸、硬脂酸和油酸)、氢化植物油、脂肪酸的甘油三酯、脂肪酸的金属盐(例如硬脂酸锌和硬脂酸镁)、乙二醇(诸如聚乙二醇)和白云母、以及它们的混合物。在一个实施方案中,本发明的组合物的润滑剂成分包含硬脂酸镁。
在一个实施方案中,每100pbw的本发明组合物含有约0.05pbw到约5pbw、更通常为约0.1pbw到3pbw、甚至更通常为约0.2pbw到约2pbw的润滑剂。
在一个实施方案中,本发明的可直接压制的钙类膳食补充剂组合物还包含崩解剂。本文中所使用的术语“崩解剂”是指基本不溶于水,但在水中可膨胀的物质。崩解剂有助于加速本发明组合物的压制品在水性介质中崩解和溶解。任何可药用的化合物只要其基本不溶于水,但在水中可膨胀,从而加速压制品(例如,由本发明的组合物制成的片剂)在水性介质中的崩解和溶解,那么这种化合物就适于用作本发明组合物的崩解剂。合适的崩解剂包括(例如)羧甲基纤维素纳、淀粉、微晶纤维素、大豆蛋白、海藻酸、交联聚乙烯吡咯烷酮(也称之为交联聚维酮)和交联羧甲基纤维素钠(也称之为交联羧甲纤维素钠)、以及它们的混合物。在一个实施方案中,本发明的组合物的崩解剂包含交联羧甲纤维素钠。
在一个实施方案中,每100pbw的本发明组合物含有约0.05pbw到约5pbw、更通常为约0.1pbw到约4pbw的崩解剂。
在一个实施方案中,每100pbw的所述可直接压制的钙类膳食补充剂组合物含有以下成分:
约15pbw到约75pbw、更通常为约30pbw到约60pbw的本发明的团聚体;
约85pbw到约25pbw、更通常为约70pbw到约40pbw的除所述团聚体之外的含钙物质(通常为磷酸三钙)的颗粒;
约0.05pbw到约5pbw、更通常为约0.1pbw到约4pbw的崩解剂;以及
约0.05pbw到约5pbw、更通常为约0.1pbw到约3、甚至更通常为约0.2pbw到2pbw的润滑剂。
本发明的可直接压制的钙类膳食补充剂组合物可用来通过常规方法(例如使用压片机)生产成品口服制剂(例如片剂和囊片),并且防止裂片(capping)。
本发明的口服制剂表现出高硬度、低脆度和良好的崩解性。本发明的咀嚼片制剂表现出好的口感和很少的粉质感及砂砾感。
本文所述的硬度是由Schleuniger 2E型片剂硬度测试仪来测量。
在一个实施方案中,本发明的口服制剂所表现出的硬度高于或等于15千克力(“kp”),更通常为约20kp到约30kp,甚至更通常为约24kp到约28kp。
在另一个实施方案中,本发明的口服制剂是咀嚼片,其所表现出的硬度高于或等于10kp,更通常为约12kp到约22kp,甚至更通常为约14kp到16kp。
本文所述的脆度是根据美国药典1216片剂脆度测试方法(USP25)来测量,并以磨损率来表示。在一个实施方案中,本发明的口服制剂所表现出的脆度低于1%,更通常低于约0.6%,甚至更通常低于约0.2%。
本文所述的“崩解”性质是根据美国药典试验方法No.701(USP26)来测量,并以时间(单位为秒)来表示,亦即,使用特定仪器,当片剂浸入37±2℃的水中时该片剂崩解成能通过试验筛网的较小碎片所用的时间。在一个实施方案中,本发明的口服制剂所表现出的崩解时间为90秒,更通常小于60秒。
本文所述的术语“裂片”是指在压制后由片剂碎片的分离或片体分层而损失了片剂的物理完整性。
实施例1-3
实施例1-3中的每种可压制的磷酸三钙团聚体都是通过对浆料进行喷雾干燥而制成的,每100pbw的所述浆料含有33.6pbw的磷酸三钙(“TCP”)颗粒、64.2pbw的水和2.2pbw的聚乙烯吡咯烷酮K30(“PVP30”)、聚乙烯吡咯烷酮K90(“PVP90”)或瓜尔豆胶三种粘结剂中的一种。
在Niro Mobile Minor实验室级的喷雾干燥器中,使用以下条件进行喷雾干燥:
调节风门(Damper) | 100%开放 |
喷雾器 | 涡轮式 |
气压 | 4kg/cm2 |
加热条件 | 设定为II |
计时器 | 100% |
在下表I中列出磷酸三钙颗粒和每一种团聚体的粒度分布。
表I
例子 | (只有TCP) | 实施例1 | 实施例2 | 实施例3 | |
粘结剂 | - | PVP30 | PVP90 | 瓜尔豆胶 | |
流速(g/s) | 19.7 | 37.3 | 22.3 | ||
体密度(g/ml) | 0.391 | 0.512 | 0.436 | 0.463 | |
振实密度(g/ml) | 0.536 | 0.640 | 0.545 | 0.634 | |
粒径(累积保留率%) | |||||
目(美国标准) | (μm) | ||||
60 | 0 | 0.1 | 0.1 | 0.1 | |
80 | 0.1 | 0.1 | 0.1 | 0.1 | |
100 | 0.1 | 0.1 | 0.1 | 0.1 | |
140 | 65.6 | 0.1 | 0.1 | 0.1 | |
200 | 85.6 | 0.1 | 0.1 | 0.1 | |
270 | 96.8 | 7.2 | 4 | 22.8 | |
325 | 98.4 | 14.4 | 12 | 36 | |
盘 | - | 100 | 100 | 100 | 100 |
实施例1B-3B和对比例C1B
将实施例1-3的团聚体与磷酸三钙、崩解剂(AC-DI-SOL,由FMC生物聚合物公司制造)以及润滑剂(硬脂酸镁)按照下表II列出的相对含量(每个含量都表示为每100pbw制剂中相应成分的pbw)混合,从而制出对比例C1B以及实施例1B、2B和3B的可直接压制的制剂。
表II
对比例C1B | 实施例1B | 实施例2B | 实施例3B | |
TCP | 97.47 | 82.36 | 82.36 | 82.36 |
TCP-C(实施例1) | - | 15.11 | - | - |
TCP-C(实施例2) | - | - | 15.11 | - |
TCP-C(实施例3) | - | - | - | 15.11 |
崩解剂(AC-DI-SOL) | 2.02 | 2.02 | 2.02 | 2.02 |
硬脂酸镁 | 0.51 | 0.51 | 0.51 | 0.51 |
总量 | 100 | 100 | 100 | 100 |
实施例1C-3C和对比例C1C
将对比例C1B和实施例1B、2B和3B中的每一种可直接压制的组合物均在压片机(Manesty Betapress)的0.312英寸×0.750英寸的圆柱形模子中进行压制,从而制成对比例C1C和实施例1C、2C和3C中的片剂。
使用Schleuniger 2E型片剂硬度测试仪来测量所述片剂的硬度,并以千克力(kp)来表示。
所述片剂的脆度是根据美国药典1216片剂脆度测试方法(USP25)来测量,并以磨损率%来表示。
所述片剂的崩解性质是根据美国药典试验方法No.701(USP 26)来测量,并以时间(单位为秒)来表示,亦即,使用特定仪器,当片剂浸入37±2℃的水中该片剂崩解成能通过试验筛网的较小碎片所用的时间。
在下表III-IV中,列出了在不同的片剂制备条件下,对比例C1C和实施例1C、2C和3C中的每一个的片剂制备条件、裂片率%和片剂性质(即厚度、硬度、脆度和崩解时间)。
表III
对比例C1C | |||||
预负荷(磅) | 400 | 800 | 800 | 800 | |
力(吨) | 1.5 | 2.0 | 2.5 | 3.0 | |
脱模力(磅) | 80 | - | - | - | |
片剂性质 | |||||
质量(mg) | 1361 | 1363 | 1362 | ||
硬度(kp) | 6.6 | 10.0 | 10.3 | - | |
厚度(英寸) | 0.303 | 0.295 | 0.291 | - | |
脆度(%) | - | - | - | - | |
裂片率(%) | 0 | 1 | 98 | - |
表IV
实施例1C | |||||
预负荷(磅) | 400 | 800 | 800 | 800 | |
力(吨) | 1.5 | 2.0 | 2.5 | 3.0 | |
脱模力(磅) | - | - | - | - | |
片剂性质 | |||||
质量(mg) | 1356 | 1375 | 1385 | 1395 | |
硬度(kp) | 7.9 | 10.9 | 13.2 | 16.5 | |
厚度(英寸) | 0.303 | 0.300 | 0.293 | 0.289 | |
脆度(%) | - | - | - | - | |
裂片率(%) | 0 | 0 | 0 | 1 |
表V
实施例2C | |||||
预负荷(磅) | 400 | 800 | 800 | 800 | |
力(吨) | 1.5 | 2.0 | 2.5 | 3.0 | |
脱模力(磅) | - | 100 | 100 | 100 | |
片剂性质 | |||||
质量(mg) | - | 1361 | 1358 | 1358 | |
硬度(kp) | - | 11.9 | 14.4 | 19.0 | |
厚度(英寸) | - | 0.299 | 0.284 | 0.283 | |
脆度(%) | - | 0.23 | 0.16 | 0.14 | |
裂片率(%) | - | 0 | 0 | 0 | |
崩解时间(s) | - | 31 | 33 | 38 |
表VI
实施例3C | |||||
预负荷(磅) | 400 | 800 | 800 | 800 | |
力(吨) | 1.5 | 2.0 | 2.5 | 3.0 | |
脱模力(磅) | - | 100 | 100 | 100 | |
片剂性质 | |||||
质量(mg) | - | 1361 | 1362 | 1364 | |
硬度(kp) | - | 11.1 | 14.6 | 17.0 | |
厚度(英寸) | - | 0.303 | 0.291 | 0.287 | |
脆度(%) | - | 0.25 | 0.16 | 0.13 | |
裂片率(%) | - | 0 | 0 | 0 | |
崩解时间(s) | - | 32 | 41 | 46 |
结果表明,含有本发明的磷酸三钙团聚体的片剂与使用常规的磷酸三钙所制成的类似片剂相比,其硬度增加。
实施例4
通过混合以下成分来制得实施例4A的可直接压制的组合物:
45.41pbw的根据上述实施例3所述的方法而制成的团聚体;
47.68pbw的TRI-TABTM磷酸三钙(得自Rhodia公司);
4.01pbw的附加粘结剂(羧甲基纤维素(PH102),得自FMC公司);
0.17pbw的维生素D3100;
2.02pbw的崩解剂(“AC-DI-SOL”,得自FMC公司);
0.24pbw的十二烷基硫酸钠,NF21(SLS,Stepanol WA-100(得自Stepan公司));以及
0.48pbw的润滑剂(硬脂酸镁)。
使用0.312英寸×0.750英寸囊片冲头(caplet punch)在压片机(Manesty Betapress)中,将实施例4A的混合物进行压制,从而制成实施例4B的囊片。
实施例4B的囊片的硬度、厚度、脆度、裂片率和崩解时间中的每一种性质都按照上述实施例1C-3C和对比例C1C所述的方法来进行测试。片剂制备条件和测试结果都列于下表VII中。
表VII
实施例4B | ||||||
力(吨) | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | |
脱模力(磅) | 70 | 100 | 120 | 140 | 160 | |
片剂性质 | ||||||
质量(mg) | 1414 | 1412 | 1415 | 1413 | 1413 | |
硬度(kp) | 14.7 | 19.9 | 27.3 | 28.8 | 31.8 | |
厚度(英寸) | 0.331 | 0.316 | 0.304 | 0.296 | 0.290 | |
脆度(%) | 0.355 | 0.247 | 0.195 | 0.176 | 0.177 | |
裂片率(%) | 0 | 0 | 0 | 0 | 0 | |
崩解时间(s) | 25 | 34 | 38 | 42 | 46 |
实施例5
实施例5的每一个咀嚼片的公称直径均为5/8英寸,公称厚度均为0.3英寸,公称质量均为2000mg,这些咀嚼片是使用5/8英寸的圆平面工具在压片机(“D”Express Press)中对以下的混合物进行压制而制成的:
42.59pbw的根据上述实施例1所列的方法而制成的团聚体;
51.69pbw的附加粘结剂(Xylitab 200(得自Danisco公司));
1.74pbw的矫味剂(SD Cherry N&A(得自Virginia Dare公司));
1.74pbw的Prosweet#875(得自Virginia Dare公司);
0.16pbw的AspartameTM(得自Searle公司);以及
2.06pbw的硬脂酸镁。
根据上面实施例1C-3C和对比例C1C中所述的方法测得实施例5的片剂的硬度为12.5kp。
在非正式的尝味试验中,发现实施例5的片剂具有最少的砂砾感和粉质感。
Claims (17)
1.一种可压制的磷酸三钙团聚体,该团聚体含有:
磷酸三钙颗粒和粘结剂,每一个所述的磷酸三钙颗粒都具有外表面,而所述的粘结剂包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶,并且所述粘结剂承载在至少一部分所述磷酸三钙颗粒的至少一部分所述外表面上。
2.权利要求1所述的团聚体,其中所述的粘结剂中所含的聚乙烯吡咯烷酮的平均分子量大于或等于约30,000。
3.权利要求1所述的团聚体,其中所述的粘结剂包含瓜尔豆胶、改性的瓜尔豆胶或它们的混合物。
4.权利要求1所述的团聚体,其中每100 pbw的所述团聚体含有:
约90 pbw到约99 pbw的所述磷酸三钙;以及
约10 pbw到约1 pbw的所述粘结剂。
5.权利要求1所述的团聚体,其中所述的团聚体为具有如下粒度分布的颗粒形式:其中少于或等于65重量%的所述颗粒具有大于325目的粒径,并且少于或等于10重量%的所述颗粒具有小于60目的粒径。
6.一种制造可压制的磷酸三钙团聚体的方法,该方法包括将磷酸三钙和粘结剂的水溶液进行喷雾干燥,所述粘结剂包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶。
7.一种可直接压制的钙类膳食补充剂组合物,每100重量份(“pbw”)的所述组合物含有:
约20 pbw到约80 pbw的团聚体,所述团聚体含有磷酸三钙颗粒和粘结剂,并且每个所述的磷酸三钙颗粒都具有外表面,而所述的粘结剂包含聚乙烯吡咯烷酮、鹿角菜胶或瓜尔豆胶,并且所述的粘结剂承载在至少一部分所述磷酸三钙颗粒的至少一部分所述外表面上;
约79 pbw到约10 pbw的一种或多种除所述团聚体之外的含钙物质的颗粒;
约0.5 pbw到约8 pbw的崩解剂;以及
约0.5 pbw到约2 pbw的润滑剂。
8.权利要求7所述的组合物,其中所述的一种或多种除所述团聚体之外的含钙物质的颗粒选自钙螯合物、钙盐或它们的混合物。
9.权利要求7所述的组合物,其中所述的一种或多种除所述团聚体之外的含钙物质的颗粒含有具有如下粒度分布的磷酸三钙颗粒:其中少于或等于15重量%的所述颗粒具有大于40目的粒径,并且少于或等于5重量%的所述颗粒具有小于325目的粒径。
10.权利要求7所述的组合物,其中所述的润滑剂选自脂肪酸、氢化植物油、脂肪酸的甘油三酯、脂肪酸的金属盐、乙二醇、白云母以及它们的混合物。
11.权利要求7所述的组合物,其中所述的崩解剂选自羧甲基纤维素纳、淀粉、微晶纤维素、大豆蛋白、海藻酸、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠以及它们的混合物。
12.一种制造钙类膳食补充剂组合物的口服制剂的方法,该方法包括对权利要求7所述的可直接压制的钙类膳食补充剂组合物进行压制。
13.一种钙类膳食补充剂组合物的口服制剂,该口服制剂是通过对权利要求7所述的组合物进行压制而制成的。
14.权利要求13所述的口服制剂,其中该口服制剂具有大于或等于10千克力的硬度。
15.权利要求13所述的口服制剂,其中该口服制剂具有大于或等于15千克力的硬度。
16.权利要求13所述的口服制剂,其中该口服制剂具有小于1%的脆度。
17.权利要求13所述的口服制剂,其中根据美国药典试验方法No.701(USP 26)所测得的所述口服制剂的崩解时间小于90秒。
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US3134719A (en) | 1962-04-05 | 1964-05-26 | American Cyanamid Co | Calcium phosphates in tablet compressing |
DE1228029C2 (de) | 1964-05-09 | 1973-05-17 | Merck Ag E | Verfahren zur Herstellung von Tabletten durch Pressen von Pulvergemischen ohne vorhergehende Granulation |
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